tbuckley/cabot-search huggingface dataset:
Abstract 2915: Intratumoral co-injections of NK cells and neutralizing antibodies against the NKG2A inhibitory pathway achieve efficacious anti-tumor responses in a CD8 T cell and cDC1-dependent manner
Authors: Maite Alvarez, Maria C. Ochoa, Carmen Molina, Alvaro Teijeira, Saray Garasa, Sandra Sanchez-Gregorio, Irene Olivera, Javier Glez-Vaz, Asunta Cirella, Gabriel Gomis, Jose Gonzalez-Gomariz, Pedro Berraondo, Ignacio Melero
Journal: Cancer Research (2023)

Abstract Local intratumoral NK cell activity is known to foster adaptive T cell-mediated immunity against cancer, that conceivably is inhibited by the interactions of the inhibitory receptor NKG2A with the MHC class I molecule HLA-E in humans or Qa-1b in mice. In this study, we found that intratumoral delivery of NK cells significantly attains therapeutic effects only if co-injected with anti-NKG2A and anti-Qa1b blocking monoclonal antibodies (mAb) in two solid mouse tumors models. Such therapeutic activity was contingent on endogenous CD8 T cells and on type-1 conventional dendritic cells (cDC1), which mediate cross-priming of tumor antigens. Moreover, the anti-tumor effects can be enhanced upon combination with anti-PD-1 mAb. This combination achieves at least partial abscopal efficacy against distant untreated tumors. In xenografted mice with HLA-E-expressing human cancer cells, intratumoral co-injection of allogeneic human NK cells and the clinical-grade anti-NKG2A mAb monalizumab synergistically achieved therapeutic effects and gave rise to stronger antibody-dependent cellular cytotoxicity (ADCC) in conjunction with cetuximab. In conclusion, these studies provide evidences for the therapeutic potential of on-site NK cell-based immunotherapies that may recruit endogenous T-cell responses. Citation Format: Maite Alvarez, Maria C. Ochoa, Carmen Molina, Alvaro Teijeira, Saray Garasa, Sandra Sanchez-Gregorio, Irene Olivera, Javier Glez-Vaz, Asunta Cirella, Gabriel Gomis, Jose Gonzalez-Gomariz, Pedro Berraondo, Ignacio Melero. Intratumoral co-injections of NK cells and neutralizing antibodies against the NKG2A inhibitory pathway achieve efficacious anti-tumor responses in a CD8 T cell and cDC1-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2915.
Abstract 2864: Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling
Authors: Hongxing Shen, Fengyuan Huang, Xiangmin Zhang, Oluwagbemiga A. Ojo, Yuebin Li, Hoa Quang Trummell, Joshua C. Anderson, John Fiveash, Markus Bredel, Eddy Yang, Christopher Willey, Zechen Chong, James Bonner, Lewis Z. Shi
Journal: Cancer Research (2023)

Abstract Therapeutic resistance to immune checkpoint blockers (ICBs) is a pressing issue, limiting ICB efficacy to a small proportion of cancer patients. Concerted efforts from our group and others have identified that loss of IFN-γ signaling genes in melanoma is a major mechanism of resistance to ICBs. However, strategies of overcoming this resistance have been largely elusive. Moreover, given the indispensable role of T cells in governing ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling impacts tumor-infiltrating T cells (TILs). In this study, we report that melanomas with defective IFN-γ signaling (IFNγR1KO) have reduced infiltration and function of TILs. Intriguingly, IFNγR1KO melanoma cells harbor a network of constitutively active protein tyrosine kinases (PTKs) centered on JAK1/2, essential downstream components of the IFN-γ signaling. Additional mechanistic studies reveal that JAK1/2 activation is mediated by augmentation of the mTOR pathway. Importantly, targeting active JAK1/2 with FDA-approved Ruxolitinib (Ruxo) selectively suppresses growth of IFNγR1KO but not scrambled control melanoma, in a T cell and host TNF-dependent manner. Together, our results highlight an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a therapeutic target that can be leveraged to bypass ICB resistance of melanomas defective of IFN-γ signaling. Citation Format: Hongxing Shen, Fengyuan Huang, Xiangmin Zhang, Oluwagbemiga A. Ojo, Yuebin Li, Hoa Quang Trummell, Joshua C. Anderson, John Fiveash, Markus Bredel, Eddy Yang, Christopher Willey, Zechen Chong, James Bonner, Lewis Z. Shi. Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2864.
Abstract 6436: 1C3, a novel non-blocking anti-human TNFR2 antibody, promotes effector T cell responses and demonstrates potent anti-tumor activity
Authors: Yongfei Yang, Shuzhen Cao, Wenjiao Zhang, Jing Zhang, Zhe Shao, Xueyuan Jiang, Qingya Duan, Maopeng Tian, Sen Mei, Zhaoxue Yu
Journal: Cancer Research (2023)

Abstract Regulatory T cells (Tregs) are a subset of immunosuppressive CD4+ T lymphocytes which can inhibit effector T cell activity in the tumor microenvironment (TME) and promote tumor growth. Depletion of Tregs is a promising immunotherapy strategy for treatment of cancers. Tumor necrosis factor receptor-2 (TNFR2) is highly expressed on both Tregs and many kinds of tumor cells, making it a potential candidate for tumor-targeted antibody therapy. A fully human, non-blocking agonist antibody to TNFR2, 1C3, was generated from RenMab™ mice, which contain the full human immunoglobulin variable domain. 1C3 was selected from a large panel of antibody candidates after unbiased, high-throughput efficacy screening conducted in syngeneic tumor mouse models established in humanized TNFR2 mice. In vitro, 1C3 effectively promoted proliferation of cytotoxic T cells. Subsequently, the in vivo anti-tumor efficacy and safety of 1C3 was evaluated in syngeneic tumor mouse models expressing human TNFR2. The results demonstrated that 1C3 monotherapy significantly inhibited tumor growth in a dose-dependent manner. In combination with anti-human PD-1 or PD-L1 antibodies, 1C3 also greatly potentiated anti-tumor responses compared to monotherapy of each agent. Analysis of tumor-infiltrating lymphocytes (TIL) demonstrated that 1C3 treatment significantly increased the ratio of effector T cells to Tregs in the TME. Moreover, 1C3 was well tolerated in mice, and no adverse effects were observed even at high doses (e.g. 100 mg/kg). In conclusion, these data demonstrate that 1C3 is a novel anti-human TNFR2 non-blocking agonist antibody with effective anti-tumor efficacy and favorable safety. 1C3 may exert these effects by regulating Treg and effector T cell activities. Citation Format: Yongfei Yang, Shuzhen Cao, Wenjiao Zhang, Jing Zhang, Zhe Shao, Xueyuan Jiang, Qingya Duan, Maopeng Tian, Sen Mei, Zhaoxue Yu. 1C3, a novel non-blocking anti-human TNFR2 antibody, promotes effector T cell responses and demonstrates potent anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6436.
Abstract 364: Multi-omics approaches revealed the involvement of immune cells in skeletal muscles of lung cancer cachexia mouse model
Authors: Se-Young Park, Bomi Kim, Myunggyo Lee, Haeseung Lee, Na-Young Song
Journal: Cancer Research (2023)

Abstract Cancer-associated cachexia (CAC) is a multifactorial syndrome characterized by loss of body weight and skeletal muscle mass that cannot be fully recovered by nutritional support. It accounts for approximately 20 % of cancer-related deaths. However, there are no approved treatments for CAC yet. In order to better understand CAC, we wanted to apply the multi-omics approaches to simultaneously assess tumors and skeletal muscles in CAC mouse models. First, we established a lung cancer cachexia mouse model by orthotopic transplantation of KRAS-mutant lung cancer cells. Lung tumor-bearing mice developed cachexia at 7 weeks post injection, showing over 20 % of body weight loss and wasting of skeletal muscles and fats. The histological and immunoblotting analyses revealed degradation of gastrocnemius (GA) and tibialis anterior (TA) muscles in CAC group. Then, we performed the bulk RNA sequencing to assess transcriptomic changes in lung tumors and GA muscles of CAC mice. In lung tumors, genes associated to ATP metabolic process was upregulated. However, skeletal muscles of CAC mice showed upregulation of genes involved in protein degradation and immune responses, while genes related to energy metabolism were downregulated. Notably, the immunohistochemical staining revealed the increased numbers of infiltrating macrophages and CD8+ T cells in skeletal muscles of CAC mice. These data suggest the involvement of immune cells in lung cancer-associated cachexia. To further identify the distinct immune cell populations involved in CAC, the single cell RNA sequencing was conducted using CD45+ immune cells infiltrated into GA muscles of CAC mice. The enrichment of natural killer cells, dendritic cells and T cells was detected in GA of CAC mice. Moreover, we confirmed the roles of the infiltrating immune cells by using the neutralizing antibodies in CAC mice. Taken together, these data suggest the involvement of the immune cells in the skeletal muscle wasting of CAC mice. These multi-omics approaches will shed light on development of therapeutics for cancer-induced cachexia. Citation Format: Se-Young Park, Bomi Kim, Myunggyo Lee, Haeseung Lee, Na-Young Song. Multi-omics approaches revealed the involvement of immune cells in skeletal muscles of lung cancer cachexia mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 364.
Abstract 6332: A humanized anti-cd40 antibody with anti-tumor pharmacological activity and cynomolgus monkey safety
Authors: Zhenyu Li, Lili Zhao, Guimin Zhang, Bin Li, Zhong Liu, Guangyan Li, Zhongsong Zhu
Journal: Cancer Research (2023)

Abstract LNF1901 is a humanized CD40 agonistic antibody. LNF1901 can bind to CD40 protein of human(EC50=23.6ng/mL) and monkey(EC50=23.5ng/mL), but cannot bind to CD40 protein of rat and mouse. LNF1901 had strong activation effect on DC cells(EC50=0.04ug/mL) and had strong ADCC and CDC effects. AT a dose of 20mg/kg, the TGITW of LNF1901 was 59.9% in Female NPG mice were inoculated with Raji/CIK/DC subcutaneous transplanted tumor model. Following intravenous infusion of LNF1901 at doses of 6, 30, or 150 mg/kg to cynomolgus monkeys weekly for 4 weeks, the highest non-severely toxic dose (HNSTD) was considered to be 150 mg/kg.LNF1901 had demonstrated manageable safety and promising antitumor activity in vivo and in vitro tests. Citation Format: Zhenyu Li, Lili Zhao, Guimin Zhang, Bin Li, Zhong Liu, Guangyan Li, Zhongsong Zhu. A humanized anti-cd40 antibody with anti-tumor pharmacological activity and cynomolgus monkey safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6332.
Abstract 3854: TNIK inhibition as a novel therapeutic in cMyc high/TTF1 low SCLC
Authors: Azusa Tanimoto, Robert J. Cardnell, Benjamin B. Morris, Kavya Ramkumar, Shen Li, Qi Wang, Allison C. Stewart, Carl Michael Gay, Jing Wang, Lauren Averett Byers
Journal: Cancer Research (2023)

Abstract Background: Small cell lung cancer (SCLC) is a highly lethal malignancy, with rapidly acquired chemotherapy resistance. Some studies have reported that Wnt signaling pathway activation promoted cell proliferation and was correlated with chemo-resistance in SCLC. None of the therapies targeting Wnt pathway components of the transmembrane and the cytoplasm have been successful in a clinical application due to toxicity and insufficient efficacy. However, targeting Wnt signaling inside the nucleus has been drawing increasing attention as cancer therapeutics. TRAF2 and NCK-interacting protein kinase (TNIK), which interacts with downstream effectors, TCF4/β-catenin transcriptional complex, is an essential activator of Wnt target genes. TNIK is highly expressed in several cancers for cell proliferation, thus TNIK is expected as a novel druggable target. On the other hand, the question remains whether TNIK is a critical target in SCLC. We hypothesize that a TNIK inhibitor has potent anti-tumor effects in SCLC and its promising biomarkers exist. Methods: We used 29 SCLC cell lines including all four subtypes defined by differential expression of transcription factors ASCL1, NEUROD1, POU2F3, and inflamed gene signature (SCLC-A, N, P, and I, respectively) to evaluate the effect of a TNIK inhibitor, NCB-0846 in vitro. We correlated NCB-0846 IC50 values with proteomic profiling (Reverse Phase Protein Array, RPPA) data. Protein expression was examined by western blotting. Results: NCB-0846 markedly reduced cell proliferation in SCLC-N and P cell lines. There was a strong positive correlation between cMyc and the efficacy of NCB-0846 (r=-0.484, P&amp;lt;0.01), while a negative correlation between TTF1 and the efficacy (r=0.569, P&amp;lt;0.01). Additionally, NCB0846 decreased the expression of cMyc in cMyc-high/TTF-1 low SCLC cells. Conclusions: These findings indicate that TNIK inhibitors may be a new personalized molecular-targeted therapy in cMyc-high/TTF-1-low SCLC. Citation Format: Azusa Tanimoto, Robert J. Cardnell, Benjamin B. Morris, Kavya Ramkumar, Shen Li, Qi Wang, Allison C. Stewart, Carl Michael Gay, Jing Wang, Lauren Averett Byers. TNIK inhibition as a novel therapeutic in cMyc high/TTF1 low SCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3854.
Abstract 2207: The prognostic role of γδ T cells in colorectal cancer and the establishment of related nomogram for predicting overall survival of the patients
Authors: Rulan Ma, Dangcheng Xue, Yong Zhang, Kun Zhu, Dawei Yuan, Tuanhe Sun, Caijing Mo, Xiaoyuan Deng, Fujun Qin, Kang Li
Journal: Cancer Research (2023)

Abstract Objective: The aim of the present study was to explore the prognostic role of γδ T cells in colorectal cancer, and establish a nomogram for predicting the overall survival of the patients. Methods: Immunohistochemistry was performed to analyze the infiltration degree of γδ T cells in tumor and normal tissues of colorectal cancer. The relationship between γδ T cells infiltration in tumor tissues and the prognosis of patients with colorectal cancer were determined by survival analysis. Cox regression analysis was performed to detect the factors related to the prognosis of patients with colorectal cancer. R software was used to establish and verify a nomogram for predicting the prognosis of patients with colorectal cancer. Results: The degree of γδ T cell infiltration in tumor tissues and normal tissues of CRC was not different (t=0.35, P=0.731). However, the infiltration of γδ T cell was related to the survival status of the patients (x2=4.88, P=0.027). Besides, the infiltrating degree of γδ T cells in tumor tissue was obviously related to the prognostic improvement of the patients with colorectal cancer (Log-rank P=0.016) and could reflect the benefit of adjuvant chemotherapy (Log-rank P=0.003). Cox regression analysis showed that tumor stage (HR:3.14, 95%CI:1.25-7.89, P=0.015), serum CEA level (HR:3.67, 95%CI:1.48-9.10, P=0.005) and γδ T cell infiltration (HR:0.38, 95%CI:0.14-0.99, P=0.049) were independent prognostic factors of overall survival in patients with colorectal cancer. A nomogram based on tumor stage, serum CEA level and γδ T cell infiltration was established and showed a good prediction ability for survival of patients with colorectal cancer. Conclusion: γδ T cell infiltration degree in tumor tissue was an important factor to improve the outcome of patients with colorectal cancer, and could predict the benefit of adjuvant chemotherapy. The nomogram had a good ability for predicting overall survival of the patients with colorectal cancer. Citation Format: Rulan Ma, Dangcheng Xue, Yong Zhang, Kun Zhu, Dawei Yuan, Tuanhe Sun, Caijing Mo, Xiaoyuan Deng, Fujun Qin, Kang Li. The prognostic role of γδ T cells in colorectal cancer and the establishment of related nomogram for predicting overall survival of the patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2207.
Abstract 5556: Lemur tyrosine kinase 3 serves as a predictor of patient outcome and a target for the treatment of ovarian cancer
Authors: Thea K. Kirsch-Mangu, Axel S. Tullberg, Anna Portela, Khalil Helou, Ghassan M. Saed
Journal: Cancer Research (2023)

Abstract The objective of these in vitro and in vivo studies was to validate Lemur Tyrosine Kinase 3 (LMTK3) as a specific target and predictor of clinical outcome in ovarian cancer. LMTK3 belongs to a family of regulated tyrosine kinases with three structurally related isoforms, LMTK1, LMTK2, and LMTK3. Both nuclear and cytoplasmic LMTK3 expressions correlated with tumor grade and patient survival in cancers such as breast and colorectal cancer. We tested the clinical significance of the LMTK3 gene by immunohistochemistry (IHC) using LMTK3 monoclonal antibody on formalin-fixed paraffin-embedded sections (FFPE) collected from 204 early-stage (stage I-II) ovarian cancer patients. Results from this IHC LMTK3 study revealed a higher cytoplasmic to nuclear localization of LMTK3 correlated with worse overall survival (P&amp;lt;0.01). Further investigation of LMTK3’s prognostic value by screening LMTK3 signaling in 270 stage III-IV ovarian cancer patients is ongoing. We utilized the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay for testing the killing efficacy of targeting LMTK3 by a monoclonal antibody, siRNA, and specific LMTK3 binding peptides (LMTK3BP) in ovarian cancer cell lines SKOV3, MDAH-2774, A2780, and TOV-21G. Treatment with LMTK3 specific monoclonal antibody, siRNA, and LMTK3BP significantly induced killing of both chemosensitive and chemoresistant ovarian cancer cells without affecting normal cells in vitro. Moreover, we observed this killing as synergistic with both Cisplatin and Taxotere treatment in vitro. Lastly, we used an A2780 cell line derived orthotopic xenograft mouse model of ovarian cancer to test the efficacy of specific LMTK3BP in vivo. Strikingly, LMTK3BP 20 mg/kg IV dose given three times a week for three weeks showed a 35% tumor reduction. Furthermore, in vivo safety studies showed no signs of toxicity of the LMTK3BP, even at a very high dose of 40 mg/kg. Thus, with dose optimization in ongoing experiments, we could expect a higher efficacy. In conclusion, this study highlighted the importance of LMTK3 as a predictor of patient clinical outcome and potential target for treatment in ovarian cancer. Citation Format: Thea K. Kirsch-Mangu, Axel S. Tullberg, Anna Portela, Khalil Helou, Ghassan M. Saed. Lemur tyrosine kinase 3 serves as a predictor of patient outcome and a target for the treatment of ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5556.
Abstract 3166: CanSig: <i>De novo</i> discovery of shared transcriptional states in cancer single cells
Authors: Josephine Yates, Florian Barkmann, Pawel Piotr Czyz, Agnieszka Kraft, Niko Beerenwinkel, Valentina Boeva
Journal: Cancer Research (2023)

Abstract Tumor heterogeneity is regarded as a significant obstacle to successful personalized cancer medicine. Specifically, multiple cancer types have been shown to exhibit heterogeneity in the transcriptional states of malignant cells even within the same tumor. Some of these specific transcriptional states of malignant cells have been linked to cancer relapse and resistance to treatment. However, today there is no universal and easy-to-use computational method to extract information about shared transcriptional states from single-cell RNA sequencing measurements (scRNA-seq). To reliably identify shared transcriptional states of cancer cells, we propose a novel computational tool, CanSig. CanSig automatically preprocesses, integrates, and analyzes cancer scRNA-seq data from multiple patients to provide novel signatures of shared transcriptional states; it also associates these states to known and potentially targetable biological pathways. CanSig jointly analyzes cells from multiple cancer patients while correcting for batch effects and differences in gene expressions caused by genetic heterogeneity. For this, CanSig automatically infers copy number variations in malignant cells and trains a deep learning architecture based on conditional variational autoencoders integrating scRNA-seq measurements. In our benchmarks, CanSig shows state-of-the-art performance in data integration and reliably re-discovers known transcriptional signatures on four previously published cancer scRNA-seq datasets. For instance, CanSig re-discovers four main cellular states of glioblastoma cells previously reported by Neftel et al., Cell, 2019. We further illustrate CanSig’s investigative potential by uncovering signatures of novel transcriptional states in several cancer types; some of the novel signatures are linked to such cancer hallmarks as cell migration and proliferation and are enriched in more advanced tumors. We also uncover signatures associated with specific genomic aberrations such as gene copy number gains. In conclusion, CanSig detects shared transcriptional states in tumors using as input scRNA-seq data for cells with different genetic backgrounds and possibly exhibiting strong batch effects. It can significantly facilitate the analysis of scRNA-seq cancer data and efficiently identify transcriptional signatures linked to known biological pathways. The CanSig method implemented in Python is available at https://github.com/BoevaLab/CanSig Citation Format: Josephine Yates, Florian Barkmann, Pawel Piotr Czyz, Agnieszka Kraft, Niko Beerenwinkel, Valentina Boeva. CanSig: De novo discovery of shared transcriptional states in cancer single cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3166.